Orthostatic tolerance is defined by the ability to maintain adequate arterial pressure and cerebral perfusion despite head-to-foot fluid shifts induced by standing or lower body negative pressure (LBNP). Syndromes such as neuro-cardiogenic syncope afflict thousands of apparently normal, healthy people every day, and greater than 50% of astronauts returning from space cannot stand passively for 10 minutes. The etiology of orthostatic intolerance is multi-factorial, but the condition is likely related to one or more of the following: 1) malfunction of arterial baroreceptors; 2) inappropriate autonomic cardiac regulation; 3) relative hypovolemia; 4) inadequate sympathetic nervous system activation; and/or 5) inadequate peripheral vascular responsiveness to sympathetic stimulation. To complicate matters, women seem to experience orthostatic intolerance to a greater extent than men. Women develop greater cardioacceleration during LBNP compared with men, less systemic vasoconstriction, and greater blood pooling in the pelvic region. Circulating estrogen levels, through activation of vasodilators such as nitric oxide, have also been implicated as a contributing factor. Therefore, the global objective of this proposal is to identify differences in cardiovascular responses to orthostatic stress between men and women, and between women during different phases of their menstrual cycle. To study the influence of gender on orthostatic tolerance, males and females will be directly compared, and the same females will be compared during different phases of their menstrual cycle with the following tests: 1) controlled frequency breathing; 2) Valsalva's maneuver; and 3) LBNP. Beat-to beat R-R interval, arterial pressure, body fluid distribution, and muscle sympathetic nerve activity will be measured during all protocols. These minimally invasive, highly integrated tests of autonomic cardiovascular control will inform fundamental cardiovascular mechanisms during orthostatic challenges, and will highlight differences associated with gender and menstrual phase. The results of the proposed research could lead to advances in the terrestrial treatment of neuro-cardiogenic syncope, and to gender-specific countermeasures to the cardiovascular deconditioning that occurs in astronauts in space. As an additional specific aim, the research is designed in large part to allow undergraduate students to receive an invaluable introduction to research.